1. Field of the Invention
The invention relates to a process for making arylacrylic acids and their esters by the palladium catalyzed coupling of a diazonium salt with an olefinic bond.
2. Background Art
Arylacrylic acid derivatives, particularly the cinnamates, have ultraviolet light-absorbing properties which make them valuable for use as UV light-absorbing agents. One of the most important UV absorbers sold in the United States and throughout the world is 2-ethylhexyl p-methoxycinnamate (octyl methoxycinnamate). Octyl methoxycinnamate is the most widely used active ingredient in all major sunscreen and suntanning lotions throughout the world and is a category I sunscreen as defined by the Tentative Final Monograph for Sunscreens. (See 21 CFR Part 352, Docket 78N0038.)
One of the most common routes to arylacrylic acid derivatives such as octyl methoxycinnamate is to react an aryl aldehyde with an acetate as set forth in Scheme I. ##STR1## This is the method by which octyl methoxycinnamate is made on a commercial basis. The major drawback of the method is the cost of the starting aldehyde, anisaldehyde. Consequently, an alternative synthesis that uses a less expensive starting material has been sought.
One available alternative is the use of the so-called "Heck reaction" which involves coupling an organopalladium intermediate with an olefin. The synthesis has been applied to octyl methoxycinnamate wherein the organopalladium intermediate is generated from p-methoxyphenyliodide and subsequently coupled with the acrylic ester, ethylhexyl acrylate, in the presence of a tertiary amine (U.S. Pat. No. 4,970,322). The drawback of the reaction when applied to the synthesis of octyl methoxycinnamate, is again the expense of the starting material p-methoxyphenyliodide. To overcome the problem, the inventors in U.S. Pat. No. 4,970,322 generated p-methoxyphenyliodide from the more economical p-anisidine via a diazonium salt. Once neutralized, the iodide can be separated and used in the Heck reaction as described above. The overall process is illustrated in Scheme II. ##STR2##
The economic viability of this process requires that the iodide and the tertiary amine be efficiently recycled. The disadvantage is that four reaction steps are required instead of one and that losses occur in each step. Clearly, it would be desirable to react the diazonium salt directly with the acrylic acid ester to eliminate a number of steps.
In theory, the palladium catalyzed coupling of an aromatic ring with an olefinic bond using a diazonium salt as the starting material is feasible. The literature on the reaction has been reviewed (R. F. Heck, "Palladium Reagents in Organic Synthesis", Academic Press, 1985, p.287-290) for a number of model systems, albeit not for the potential synthesis of octyl methoxycinnamate. As a practical matter, however, no successful commercial process utilizing the diazonium salt has been developed. This is due primarily to the fact that the most commercially feasible way of preparing the salt is in an aqueous solution which is generally immiscible with the olefinic substrate. This immiscibility results in either no reaction or a greatly diminished rate of reaction. The latter has many disadvantages, the most significant of which is that side reactions, such as hydrolysis of the diazonium salt to the phenol, can efficiently compete with the coupling reaction.
What emerges from the prior art is that attempts to overcome the immiscibility problem by the use of organic solvents which had some water miscibility, were only moderately successful. It was found that improved yields could be achieved only if the diazonium salt was first isolated as the tetrafluoborate salt and then separately reacted with the olefin under anhydrous conditions. Expense and safety considerations connected with the use of fluoroboric acid and the undesirability and safety considerations of isolating the diazonium salt make such a route commercially unfeasible.
This need to exclude water from the coupling reaction led to an alternative procedure where the diazonium salts were made in the absence of water. t-Butyl nitrite was used to form the diazonium moiety rather than sodium nitrite which requires aqueous media. (K. Kikukawa et al., J. Org. Chem., 46, (1981), 4885.) While such a method is suitable for a laboratory synthesis, it is not suitable for commercial manufacture.
An additional disadvantage of the prior art processes is that they all require relatively large amounts of the palladium catalyst, i.e., from about 1.0 mole % to about 10 mole % (see Heck Supra; K. Kikukawa et al., Tetrahedron, 37 (1981)31). The values refer to the amount of catalyst with respect to the amine. At the 2 mole % level, even when the catalyst is recovered and recycled, the catalyst cost becomes equivalent to the total cost of all other materials used. These values are excessively high for an economically viable commercial process, particularly for the manufacture of a UV-light absorbing agent.
Thus the prior art does not teach or suggest a palladium catalyzed addition of a diazonium salt to a double bond which would have any commercial potential. The need for anhydrous conditions and an excessive amount of palladium catalyst to obtain reasonably high yields, make all such processes prohibitively expensive.